Abdominal aortic aneurysm (AAA) affects 5-10% of the male and females over the age of 65 and is the 13*^ leading cause of death in the United States. AAA, defined as a permanent localized dilation in the arterial wall with a diameter greater than 50% of normal, is an inflammatory disease of the aorta that can result in dissection of the wall, formation of an intramural clot, and rupture of the aorta resulting in almost immediate death in the majority of cases. Importantly, the role of the intramural clot in the etiology of AAA remains poorly explored. We will test the two specific hypotheses that formation of an intramural clot stabilizes early AAAs while conversely resulting in detrimental inflammation and protease activity in late-stage AAAs. Specifically, I will investigate the roles of tissue factor (TF), thrombin, platelets, and protease activated receptors (PARs) in the formation and progression of AAAs. We will utilize the angiotensin II (Angll) LDLr-/- mouse model of AAA. We will use both genetic and pharmacologic approaches to modulate the expression and activity of different proteins and determine the effect on AAA. My proposal is divided into four aims, the first two being mentored and the last two being independent. Aim 1 will examine the role of platelets and the thrombin receptor on platelets (PAR-4) in AAA initiation. We hypothesize that decreased PAR-4-dependent activation on platelets or anti-platelet therapy will reduce clot formation and increase AAA rupture. Aim 2 will examine the intervention of anti-platelet drugs on AAA progression. We hypothesize that decreased platelet activation results in less inflammation, matrix metalloproteinase activity, and subsequent rupture. Aim 3 will determine the role of TF in Angll-induced AAA progression and rupture. We hypothesize that decreased TF coagulant activity will reduce clot formation that promotes AAA rupture, and reduced TF and PAR-2 expression by vascular smooth muscle cells (VSMCs) will result in expansion of AAAs due to reduced VSMC migration. Aim 4 will determine the role of thrombin and the downstream effectors fibrinogen and PAR-1 in AAA. We hypothesize that fibrinogen deficiency and anticoagulant therapy will decrease clot formation and lead to an increase in AAA rupture and, that PAR-1 deficiency will increase AAA due to decreased VSMC migration. Together, these studies will increase our understanding of the role of the coagulation cascade, platelets and PARs in the initiation, progression, and rupture of AAAs. The clinical significance of this work is that use of anti-thrombotic drugs may increase or decrease the risk of AAA rupture in patients in a temporal manner.